Synthesis of Benzofused Azoles Using MontmoriloniteK-10 Catalyst
A Dissertation
Submitted in partial fulfilment for the degree of
MASTER OF SCIENCE IN CHEMISTRY
Under Academic Autonomy
NATIONAL INSTITUTE OF TECHNOLOGY ROURKELA
Submitted Jointly By
RAJENDRA KUMAR SAHA
Roll no: 410CY2028
RAJIB KUMAR DEY
Roll no: 410CY2009
DEPARTMENT OF CHEMISTRY
NATIONAL INSTITUTE OF TECHNOLOGY, ROURKELA
ODISHA - 769008
NATIONAL INSTITUTE OF TECHNOLOGY, ROURKELA
DECLARATION
We hereby certify that the work which is being presented in the thesis entitled “Synthesis of
Benzofused Azoles Using
Montmorilonite K-10 Catalyst” in partial fulfillment of the
requirement for the award of the degree of Master of Science, submitted in the Department of
Chemistry, National Institute of Technology, Rourkela. The work is done for the training purpose
and is a repetitionwork done by Ph. D. scholar Mr. Raghavender carried out under the supervision
of Dr. Niranjan Panda.
The matter embodied in this thesis has not been submitted by us for the award of any other
degree.
Date:
(Rajendra Kumar Saha)
(Rajib Kumar Dey)
1
Acknowledgements
It is impossible to thank all the people who have helped us a lot but they know who they are
and we are deeply grateful to all of them.
Several deserve special mention. My teachers Prof. Dr. Niranjan Panda and Ph.D.scholars
Mr. Ashis Kumar Jena and Mr. M. Raghabendra who helped and supported us every inch of the
way. Special thanks to Department of Chemistry NIT Rourkela.
Thanks all our classmates and friends for their support and encourage .
Thanks too, to all our family members who have all supported me on my journey.
Finally, thanks to all our good wishers. It has been a pleasure to work on chemistry in National
Institute of Technology, Rourkela.
2
Introduction
Heterocycles occupies a central position in organic chemistry and considerable attention
has been focused on their synthesis. In particular the benzofused nitrogen containing heterocycles
are a common heterocyclic scaffold in many biologically active and medicinally significant
compounds.1 Apart from they have been used as ligands for organometallic reactions, in
semiconductors and dye molecules. Due to the wide applications of these class of heterocycles in
medicine, materials and biology, chemist are interested for their synthesis.
Benzoxazoles (Fig-1, a) are privileged organic compounds of medicinal significance,
found in many natural products and are used in drug discovery programme. For example this core
structure
is
found
in
many
cytotoxic
natural
products
such
as
the
antimycobacterialpseudopteroxazole, UK- 1, AJI9561 (Figure 2). They have been used as
cathepsin S inhibitor, 5-HT receptor agonist, HIV reverse transcriptase inhibitor L-697661,
estrogen receptor-agonist ERB-041, selectiveperoxisome
proliferator-activated
receptor
γ
antagonist JTP- 426467, anticancer agent NSC-693638 and orexin-1 receptor antagonist SB3348672. Besides its use in medicinal chemistry, these are recognized as fluorescent probes such
as anion and metal cation sensors,3 as photochromatic agents and laser dyes.Similarly because of
the wide applications benzimidazole (fig-1,b) also found much attention for the development of
efficient and practical methods for the synthesis of such heterocycles.
O
H
N
N
N
benzimidazole
benzoxazole
Figure-1
(a)
(b)
3
Figure 2
CH3
O
O
N
H
H 3C
N
N
R1 O
H
N
O
O
N
RO
CH 3
H 3C
N
O
CH3
O
N
R2
CH 3
Pseudopteroxazole
H
N
SB-334867
R1=CH3 R2=H UK1
R1=H R2=CH3 AJI9561
Cl
O
N
O
N
O
NH
N
CH3
N
H
N
H 3C
NO 2
JTP-426427
NSC-693638
O
N
N
SO2
N
F
O
H
N
N
N
Antihepatitis B
N
NO 2
OCH3
Astemizole
4
HO
O
N
N
N
O
O
NH 2
NH 2
H 2N
N
N
N
N
HN
H
N
HO
S
O
O
P O
O
O
O
Lamivudine(3-TC)
HO
Entecavir
Adefovir dipivoxil
O
O
There are two major approaches for the synthesis of such heterocycles. Thefirst one
involves the coupling of 2-aminophenols or 1,2-arylamine with carboxylic acid derivatives under
strongly acidic conditions such as boric acid or polyphosphoric acids.4(Scheme-1)
Scheme-1
OH
R2COOH
O
R
R2
R
NH2
N
Condensation under
strong acidic and/high
temperature condition
The second approach involves the oxidative cyclization of immine intermediates formed by the
coupling of 2-aminophenol/o-phenylenediaminewithaldehyde.5(Scheme-2)
Scheme-2
OH
R
ArCHO
OH
0
NH2
MeOH , 45 C
O
R
R
N
Ar
N
H
Ar
DDR
CH2Cl2
O
Ar
R
N
5
Moreover harsh reaction conditions, use of toxic reagents and high reaction temperature often
limit these conventional strategies towards their synthesis.
Batey and co-workers synthesized the benzoxazole derivatives by the copper catalyzed domino
acylation-intramolecular cross-coupling strategy using 2-bromoaniline with benzoyl chloride
derivatives under microwave irradiation6.
O
Br
Cl
R
NH2
CuI, 1,10-Phen
O
Cs2CO3, MW
N
R
Nagasawa and co-workers synthesized the benzoxazole derivatives by the intramolecular
oxidative coupling using copper triflate as the catalyst7.
H
N
R
Ar
N
Cu(OTf)2
Ar
O
O
O2, O-xylene
Lingaiah and co-workers synthesized the benzoxazole by reacting the 2-aminophenol with
ethylorthoformate using silica-supported tin exchanged silicotungstic acid catalyst8.
OH
HC-(OEt)3
NH2
STA/SiO2
O
CH3CN
N
A copper catalyzed cascade aryl amination/condensation approach was done by Ma and
co-workers for the synthesis of benzimidazole derivatives using 2-iodoacetanilides with amine9.
NHCOR
R1
R2-NH2
I
N
CuI. L-proline
R1
DMSO
R
N
R2
Penget.al. developed copper catalyzed intramolecualar C-N cross-coupling
towards the synthesis of benzimidazole10
6
strategy
X NH
N
H
Cu2O, DMEDA
N
K2CO3
N
H
R1
R1
Although these results are promising, but use of metals and ligands often limits the utility of above
procedure and keeps enough room for further investigation. Here we present a simple reusable catalytic
system for the synthesis of benzoxazoles and benzimidazoles. Our approach to such systems are shown in
scheme-3
Scheme-3:
XH
HC-(OEt)3
Heterogeneous
catalytic system
X
N
NH2
X=O, NH
Recentlymontmorillonite (mont) have received much attention recently as a heterogeneous acidic
catalyst due to their properties ofcation exchange ability in their expansible interlayer space, and
due to tunable acidity11. Montmorillonite, an abundant naturally occurring clay, of negatively
charged, two-dimensional aluminosilicate layers holding exchangeable cationic species, mostly
sodium ions. The enhanced selectivity of montmorilonite comes from their lamellar swelling
structure, large surface area, availability of both Bronsted and Lewis surface acidic sites, and
redox properties12-15. The sodium ions in the clay are substituted by protons and it becomes acidic
and has been utilized in various acid-catalyzed organic reactions. Also, the use of the solid
catalyst in liquid-phase organic synthesis gives promising advantages due to its easy of separation
and can be reused after activation rather than other homogeneous acids, such as H2SO4. Due to
the potentiality of reaction of these solid catalysts(mont k 10) of high selectivity they are mostly
studied and found useful in many reactions, viz., the synthesis of γ-lactones16 , the synthesis of
fused heterocycles,17, the Friedel-Crafts reaction,18acetal and ketaldeprotection reactions,19
selective bromination of alkyl benzenes,20,etc. Acidic catalyst k-10 releases H+ which activates
the orthoester towards the nucleophilic attack of the NH2 group. Further activation and
subsequently
intramolecular
cyclisation
gives
7
the
corresponding
benzoxazoles
and
benzimidazoles respectively. Here we took montmorilonite as a heterogeneous support for the
condensation of aminophenols or o-phenylenediamines with orthoformate and leads to
benzoxazole and benzimidazole in appreciable yield (Scheme 4). .
Scheme-4:
NH2
HC-(OEt)3
OH
NH 2
Montomorilonite K-10
N
MeOH, 12h, reflux
O
Montomorilonite K-10
HC-(OEt) 3
NH 2
MeOH, rt, 3h
N
N
H
67%
Preparation of Benzoxazole
100mg(1mmole) of 2-aminophenol was stirred in methanol. To the resulting solution
trietylorthoformate 407.5 mg (3 mmol) was added followed by addition of 100 mg of
montmorilonite k-10. The resulting mixture was refluxed for 12 h. The progress of the reaction
was monitored by TLC.The reaction mixture was then filtered and the filtrate was poured in
distilled water. The organic layer was extracted with chloroform and dried over Na2SO4 and
concentrated under pressure. Unfortunately we could not isolate the pure compound.
Preparation of Benzimidazole
Following the above procedure, the benzimidazole was prepared by reacting 100mg(1mmole) of
o-phenylenediamine with triethylorthoformate 546.5mg(3mmole) in methanol solvent over k-10
catalyst at room temperature.
H NMR (400 MHz, CDCl3), δ (ppm): 7.90 (s, 1H), 7.52-7.44 (m, 2H), 7.10-7.04 (m, 2H), 5.34
(s, 1H)
1
C NMR (400 MHz, CDCl3), δ (ppm): 141.1 (d), 137.9 (s), 122.1 (d), 115.4 (d)
13
8
Conclusion
Inconclusion we have prepared the benzofuzed nitrogen-containing heterocycles using
montomorilonite k-10 as the catalyst. This catalytic process was simple and environmental safe.
Further investigation for the development of suitable catalytic systems for the synthesis of
substituted benzoxazoles and benzimidazoles are under progress
9
References
(1)(a) Sondhi, S. M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Bioorg. Med. Chem.
2006,14, 3758.
(b) Vinsova, J.; Cermakova, K.; Tomeckova, A.; Ceckova, M.; Jampilek, J.; Cermak, P.;
Kunes, J.; Dolezal, M.; Staud, F. Bioorg. Med. Chem. 2006, 14, 5850.
(c) Gong, B.; Hong, F.; Kohm, C.; Bonham, L.; Klein, P. Bioorg. Med. Chem. Lett.
2004,14, 1455.
(2) Russell D. Viirre; GhotasEvindar ;Robert A. Batey. J. Org. Chem. 2008, 73, 3452.
(3)Reiser A.; Leyshon L. J.; Saunders D.; Mijovic M. V.; Bright A.; Bogie J. J. Am. Chem. Soc.,
1972, 2414
(4) (a)Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982, 484;
(b) Hein, D. W.; Alheim,
R. J.; Leavitt, J. J. J. Am. Chem. Soc. 1957, 79, 427.
(5) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951.
(6) Batey, K. D.; Paddison, S. J.; Spohr, E.; Schuster, M. Chem. Rev. 2004, 104, 4637..
(7) Nagasawa, K. D.; Fuchs, A.; Ise, M.; Spaeth, M.; Maier, J. Electrochim. Acta1998, 43, 1281.
(8) Lingaih, M.; Meyer, W. H.; Wegner, G.; Herz, H. G.; Ise, M.; Schuster, M.; Kreuer, K. D.;
Maier, J. Solid State Ionics 2001, 145, 85.
(9) Ma, M.; Laasonen, K.; Sprik, M.; Parrinello, M. J. Phys. Chem. 1995, 99, 5749.
(10) Peng, J.; Cuijuan, M.Y.; Zong. C,; Hu F.; Feng. L.; Wang.X.;Wang.Y.; Chen.C.; J. Org.
Chem. 2011, 76, 716.
(11) (a) Pinnavaia, T. J. Science 1983, 220, 365.
(b) Laszlo, P. Acc. Chem. Res. 1986, 19, 121.
10
(c) Izumi, Y.; Onaka, M. AdV.Catal. 1992, 38, 245
(12) (a) Choudary, B. M.; Vasantha G.; Sharma, M; Bharathi, P. Angew. Chem., Znt. Ed. Engl.
1989, 28, 465.
(b) Choudary, B. M.; Bharathi, P. J. Chem. SOC., Chem. Commun. 1987, 1505.
(c) Kumar, K. R.; Choudary, B. M.; Jamil, Z.;Thyagarajan, G.J . Chem. SOC.C, hem.
Commun.1986, 130.
(d) Choudary, B. M.; Kumar, K. R.; Jamil, Z.; Thyagarajan, G. J. Chem. Soc., Chem. Commun.
1985, 931.
(e) Choudary, B. M.; Rani, S. S.; Narender, N. Catal. Lett.1993,19, 299.
(13)Valli, V. L. K.; Alper, H. J. Am Chem. SOC. 1993, 115, 3778.
(14) Farzaneh E.; Pinnavaia, T. J. Znorg. Chem. 1983,22, 2216.
(15) Cornelis, A.; Laszlo, P. Synlett 1994, 155.
(16) Roudier, J.-F.; Foucaud, A. Tetrahedron Lett. 1984, 25, 4375.
(17) Chunchatprasert, L.; Rao, K. R. N.; Shannon, P. V. R. J. Chem. Soc., Perkin. Trans. 1 1992,
1779.
(18) Sieskind, O.; Albrecht, P. Tetrahedron Lett. 1993, 34, 1197.
(19) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.; Taylor, R. L. K. Tetrahedron
Lett. 1997, 38, 1881.
(20) Venkatachalapathy, C.; Pitchumani, K. Tetrahedron 1997, 53, 2581.
11